title: Slow accumulation of mutations in Xpc-/- mice upon induction of oxidative stress.
abstract: XPC is one of the key DNA damage recognition proteins in the global genome repair route of the nucleotide excision repair (NER) pathway. Previously, we demonstrated that NER-deficient mouse models Xpa(-/-) and Xpc(-/-) exhibit a divergent spontaneous tumor spectrum and proposed that XPC might be functionally involved in the defense against oxidative DNA damage. Others have mechanistically dissected several functionalities of XPC to oxidative DNA damage sensitivity using in vitro studies. XPC has been linked to regulation of base excision repair (BER) activity, redox homeostasis and recruitment of ATM and ATR to damage sites, thereby possibly regulating cell cycle checkpoints and apoptosis. XPC has additionally been implicated in recognition of bulky (e.g. cyclopurines) and non-bulky DNA damage (8-oxodG). However, the ultimate contribution of the XPC functionality in vivo in the oxidative DNA damage response and subsequent mutagenesis process remains unclear. Our study indicates that Xpc(-/-) mice, in contrary to Xpa(-/-) and wild type mice, have an increased mutational load upon induction of oxidative stress and that mutations arise in a slowly accumulative fashion. The effect of non-functional XPC in vivo upon oxidative stress exposure appears to have implications in mutagenesis, which can contribute to the carcinogenesis process. The levels and rate of mutagenesis upon oxidative stress correlate with previous findings that lung tumors in Xpc(-/-) mice overall arise late in the lifespan and that the incidence of internal tumors in XP-C patients is relatively low in comparison to skin cancer incidence.
authors.affiliation: National Institute for Public Health and the Environment, Center for Health Protection, Bilthoven 3721 MA, The Netherlands; Leiden University Medical Center, Department of Toxicogenetics, Leiden 2300 RC, The Netherlands.
authors.forename: Joost P M
authors.initials: JP
authors.lastname: Melis
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.forename: Edwin
authors.initials: E
authors.lastname: Zwart
authors.forename: Joke
authors.initials: J
authors.lastname: Robinson
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.forename: Conny T M
authors.initials: CT
authors.lastname: van Oostrom
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D059645:Mutation Rate; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C501002:Xpc protein, mouse; D010269:Paraquat
keywords: BER; Carcinogenesis; DEHP; GG-NER; MEF; Mutagenesis; Nucleotide excision repair; Oxidative DNA damage; TC-NER; XP; Xpa; Xpc; base excision repair; di(2-ethylhexyl)phthalate; global genome nucleotide excision repair; mouse embryonic fibroblast; transcription coupled nucleotide excision repair; xeroderma pigmentosum; xeroderma pigmentosum group A; xeroderma pigmentosum group C